KR20030025302A - Process for the preparation of 5-hydroxymethyl-2-oxazolidinone and novel intermediate - Google Patents

Abstract

The present invention relates to the preparation of 5-hydroxymethyl-2-oxazolidinone (compound 1) in optically active form from 3,4-boronic acid ester (compound 2) of 3-4-dihydroxy butyramide . These oxazolidinones are very important in the pharmaceutical industry, especially in the field of antimicrobials and behavioral diseases.

Description

Production process of 5-hydroxymethyl-2-oxazolidinones and novel intermediates {PROCESS FOR THE PREPARATION OF 5-HYDROXYMETHYL-2-OXAZOLIDINONE AND NOVEL INTERMEDIATE}

Optically pure-5-hydroxymethyl-oxazolidinone is a reagent such as phosgene, ethyl chloroformate, carbonyl imidazole, 3-amino-1,2-dihydroxypropane (3-amino-1,2- Propanediol) can be obtained by carbonylation. This carbonylation reaction can also be carried out electrochemically. In any case, a method of preparing an optically active amino-diol should be designed and carbonylated.

General methods for the synthesis of oxazolidinones from vicinal amino alcohols:

Catalytic Oxidation-Bartolo Gabriele, Giuseppe Salerno, Donatella Brindisi, Micro Costa, and Gian Paolo Chiusoli, Organic Letters 625-627 (2000)-"Synthesis of 2-oxazolidinones by Direct Palladium-Catalyzed Oxidative Carbonylation of 2-Amino- 1-alkanols ";

2. diethyl carbonate-Danielmeier, K .; Steckhan E.-"Efficient Pathways to (R) -5-hydroxymethyl-2-oxazolidinone and (S) -5-hydroxymethyl-2-oxazolidone and some derivatives", Tetrahedron-Asymmetr 6: (5) 1181-1190 (may 1995 ).

3. Carbonyldiimidazole-Warmerdam EGJC, Brussee J., Vandergen A., Kruse, CG, "Synthesis of (R) -5- (hydroxymethyl) -3-isopropyloxazolidin-2-one and (S) -5- ( hydroxymethyl) -3-isopropyloxazolidin-2-one, Intermediate in the preparation of optically-active beta-blockers ", Helv Chim Acta 77: (1) 252-256 (1994);

4. Eckert, H., Forster, B., "Triphosgene, A crystalline phosgene substitute", Angew. Chem. Int. Ed. 26: (9) 894-895 (Sept 1987); and Seneci, P., Caspani, M., Ripamonti F., Ciabatti, R., "Synethesis and Antimicrobial Activity of Oxazolidin-2-ones and Related Heterocycles", J. Chem. Soc. Perk T 1 (16) 2345-2351 (August 21, 1994).

Oxazolidinone has been developed in drug development, particularly in the field of antimicrobials (Diekema, DJ, et al., Drugs 59 7-16 (2000)) and behavioral diseases (Brenner, R., et al., Clin. Therapeut. 22 4 411-419 (2000) has emerged as a very important compound. They are vancomycin-resistent enterococci , methicillin-resistant Staphylococcus aureus , cephalosporin-resistant Streptococcus pneumoniae -resistant and penicillin-resistant It is particularly effective against some resistant human pathogens, including some microorganisms (Diekema, DJ, et al., Drugs 59 7-16 (2000)). Lineezolides having the formula below are particularly recommended for the treatment of infections from antibiotic resistant bacterial strains that are resistant to vancomycin.

Optically active 3,4-dihydroxybutyl acid and 3-hydroxy-γ-lactone are important sources of chirality. They can be obtained in commercial content from carbohydrates such as starch, lactose, maltodextrin, cellulose, arabinose by oxidative decomposition (Hollingsworth, RI Biotechnology Annual Review 2 281-291 (1996); Hollingsworth, RI, J. Org. Chem) 64 7633-7634 (1999); US Patents 5,292,939, 5,808,107, 5,319,110, 5,374,773). Although 3,4-dihydroxybutyramide can be easily obtained from acid and lactone, the hofmann reaction cannot be directly applied due to the interference of 4-hydroxyl groups.

The present invention provides a method for masking and de-masking such functional groups. This method of de-masking during the conversion is very useful. This is achieved using boronic acid esters.

The present invention relates to the preparation of 5-hydroxymethyl-2-oxazolidinone (Compound 1) from novel cyclic boronic acid esters of 3-4-dihydroxy butyramide. Starting esters have the following formula:

Where r is a non-interfering functional group.

Preferred oxazolidinones have the formula:

Summary of the invention

The present invention relates to a process for preparing 5-hydroxymethyl-2-oxazolidinone, wherein the process consists of:

(a) The 3,4-cyclic boronic acid ester of 3,4-dihydroxy butyramide is reacted with alkali metal or alkaline earth metal hypohalite or alkali metal or alkaline earth metal hydroxide to give 5- Obtaining hydroxymethyl-2-oxazolidinone;

(b) 5-hydroxymethyl-2-oxazolidinone is separated from the reaction mixture.

The present invention also relates to another process for preparing 5-hydroxymethyl-2-oxazolidinone, wherein the process consists of:

(a) In the reaction mixture, 3,4-dihydroxy butyramide reacts with R boronic acid dissolved in a solvent to obtain a cyclic boronic acid ester, where R is an alkyl or aryl group having 1 to 20 carbon atoms ego;

(b) the cyclic boronic acid ester is reacted with a hypohalite and a base dissolved in an aqueous solution to obtain 5-hydroxymethyl-2-oxazolidinone;

(c) 5-hydroxymethyl-2-oxazolidinone is separated from the reaction mixture.

Another advantage of this method is that the conditions under which the boronic acid esters are formed are not very stringent and a moderate amount of water can be tolerated. Another advantage of this method is that the carbonyl fragment of the amide does not disappear during rearrangement and survives to the carbonyl group on the oxazolidinone ring. This is the only case in which oxazolidinone is produced directly by Hoffman rearrangement in protected dihydroxybutyramide. In this method, the multistep process is reduced to a single one-pot process.

The present invention relates to Hoffman reactions and related reactions, such as curtius, lossen, beckman, and the like, in which adversely located free hydroxyl groups form and induce an electro-deficient nitrogen species. A method of preventing participation in the Schmidt reaction is presented.

In particular, the present invention provides a method for blocking the participation of hydroxyl groups in the Hoffman reaction, which can be de-blocked during the desired conversion process since no separate de-blocking sequence is required.

purpose

It is an object of the present invention to obtain 5-hydroxymethyl-2-oxazolidinone, for example, in high yield from 3,4-dihydroxybutyramide, without the need for performing complex protection / deprotection steps and carbonylation steps. S) -5-hydroxymethyl-2-oxazolidinone (compound 1) is manufactured.

Another object of the present invention is to propose a process that is economical and easier to implement. This purpose is made clear by the following detailed description.

Description of Appropriate Embodiments

The aromatic or aliphatic boronic acid esters of optically pure 3,4-dihydroxybutyramide are converted directly to optically pure 5-hydroxymethyl-oxazolidone by Hoffman rearrangement in a single step. Protected amino-diols can be prepared by the methods described for other protected 3,4-dihydroxybutyramides (Wang, G., et al., J. Org. Chem. 64 1036-1038 (1999)). Not obtained. Separate carbonylation with phosgene, ethyl chloroformate or other similar reagents can be avoided.

The novel process is illustrated in Scheme I:

Where R is a non-interfering functional group.

Only two steps are essential to the process. The first step is the preparation of boronic acid ester (compound 3) from dihydroxybutamide (compound 2). The amide is obtained in quantitative yield by reacting 3-hydroxy-γ-butyrolactone with aqueous ammonia at room temperature (Wang and Hollingsworth, J. Org. Chem. 64 1036-1038 (1999)). The second step is the rearrangement of the ester under Hoffmann conditions, where the intermediate cyclic boronic acid ester isocyanate (compound 4) is converted to the ring-opened form (compound 5) and the neighboring hydroxyl groups participate. Preferred two-phase systems of water and water-miscible organic solvents protect the final product from base hydrolysis. This directly yields hydroxymethyl oxazolidinone (Compound 1) with> 90% separation yield and> 99% optical purity. This results in enormous economic advantages over the synthesis of optically pure 5- (hydroxymethyl) -2-oxazolidinone from starch, malcose, lactose or similar 4-linked carbohydrate sources through the necessary 3-4 steps. .

The alkali metal can be sodium, potassium or lithium. The alkaline earth metal may be calcium or magnesium. Hypohalite is used in excess of 2 to 6 to 1 compared to boronic acid ester. Although OCl ⁻ is suitable, hypobromite can be used.

The solvent is a two-phase water / organic system. Suitable organic solvents are tetrahydrofuran, ether dioxane or alcohols. The solvent is removed by evaporation and the volatile acid dissolved in methanol is added to remove the boronic acid formed from the volatile trimethyl ester. Reaction temperature is approximately 10-50 degreeC.

Boronic acid has an R functional group in alkyl or aryl form having 1 to 20 carbon atoms. Other non-interfering functional groups may also be used that do not participate in the reaction.

Preparation of (S) -5-hydroxymethyl-2-oxazolidinone (Compound 1):

Typical procedure for preparation and separation: 0.5 g of phenylboronic acid ester of 3.4-dihydroxybutyramide is dissolved in 20 ml THF. To the solution is added 10 ml of 13% hypochlorite sodium. The mixture is stirred at room temperature for 12 hours, after which the realignment is confirmed by NMR spectroscopy. Then the reaction mixture is concentrated and 1 ml 2N HCl and 100 ml methanol are added to the flask. The mixture is rotary evaporated until dry. This addition and removal of methanol is repeated three times to remove all boronic acid. The residue is extracted several times with acetone. The extracts are collected and concentrated once more to remove all solvents. The residue is then partitioned in a mixture of dichloromethane and water. The aqueous layer is concentrated to give 5-hydroxymethyl-2-oxazolidinone as a light brown solid: yield: 0.27 g (93.8%). The crude material can be purified by recrystallization from ethanol and dichloromethane: mp 89.0-90.0. MH ⁺ : 118.16

¹ H NMR (300 MHz, CD ₃ OD) δ ppm: 4.70 (m, 1H), 3.76 (dd, 1H, J = 12.4, 3.6 Hz), 3.64 (m, 2H), 3.44 (dd, J = 8.7, 6.6 Hz). ¹³ C NMR (75 MHz, CD ₃ OD) δ ppm: 162.4, 78.6, 63.5, 42.8. FTIR, wave number, cm ⁻¹ 3309, 1734, 1437, 1247, 1084, 1029, 771.α ²⁵ _D = 38.4, ethanol, c = 1.35, α ²⁵ _D = 48.4, methanol, c = 0.5, Lit ²⁰ α ²⁵ _D = 39, ethanol, c = 2.7, α ²⁰ _D = 48, c = 1.0, methanol. The optical purity of the compound was> 99.9% ee in GC analysis of the (S)-(-)-α-methoxy-α- (trifluoromethyl) phenylacetic acid derivative.

The foregoing description is intended to illustrate the invention and does not limit the invention, which is limited only by the claims appended hereto.

Claims (9)

Process for producing 5-hydroxymethyl-2-oxazolidinone, comprising: (a) The 3,4-cyclic boronic acid ester of 3,4-dihydroxy butyramide is reacted with alkali metal or alkaline earth metal hypohalite or alkali metal or alkaline earth metal hydroxide to give 5- Obtaining hydroxymethyl-2-oxazolidinone; (b) 5-hydroxymethyl-2-oxazolidinone is separated from the reaction mixture. Process for producing 5-hydroxymethyl-2-oxazolidinone, comprising: (a) The 3,4-dihydroxy butyramide of the reaction mixture is reacted with R boronic acid dissolved in a solvent to obtain a cyclic boronic acid ester, wherein R is an alkyl or aryl group having 1 to 20 carbon atoms ; (b) the cyclic boronic acid ester is reacted with a hypohalite and a base dissolved in an aqueous solution to obtain 5-hydroxymethyl-2-oxazolidinone; (c) 5-hydroxymethyl-2-oxazolidinone is separated from the reaction mixture. The process according to claim 1 or 2, wherein the 3,4-dihydroxybutyramide and 5-hydroxymethyl-2-oxazolidinone are optically pure. The process of claim 1 wherein the alkali metal hydroxide is sodium. The process according to any one of claims 1 to 4, wherein the hypohalite is hypochlorite. The process according to claim 1, wherein a volatile acid is added to the reaction mixture together with methanol to volatilize the trimethyl boronic acid ester from the reaction mixture. The process according to any one of claims 1 to 3, wherein the molar ratio of hypohalite and boronic acid ester is 2 to 6 to 1. The method of claim 1, wherein the alkali metal is selected from lithium, sodium, potassium, mixtures thereof, the alkaline earth metal is selected from magnesium, calcium, mixtures thereof, and hypohalite is hypochlorous acid. And hypobromic acid. The process according to any one of claims 1 to 3, which is carried out at a temperature of 10 to 50 ° C.